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APC / C C dh1 controls Ct IP stability during the cell cycle and in response to DNA damage
Author(s) -
Lafranchi Lorenzo,
Boer Harmen R,
Vries Elisabeth GE,
Ong ShaoEn,
Sartori Alessandro A,
Vugt Marcel ATM
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489017
Subject(s) - dna damage , biology , dna repair , microbiology and biotechnology , genome instability , cell cycle checkpoint , dna , ubiquitin ligase , cell cycle , homologous recombination , dna ligase , ubiquitin , cell , genetics , gene
Human cells have evolved elaborate mechanisms for responding to DNA damage to maintain genome stability and prevent carcinogenesis. For instance, the cell cycle can be arrested at different stages to allow time for DNA repair. The APC / C C dh1 ubiquitin ligase mainly regulates mitotic exit but is also implicated in the DNA damage‐induced G 2 arrest. However, it is currently unknown whether APC / C C dh1 also contributes to DNA repair. Here, we show that Cdh1 depletion causes increased levels of genomic instability and enhanced sensitivity to DNA ‐damaging agents. Using an integrated proteomics and bioinformatics approach, we identify Ct IP , a DNA ‐end resection factor, as a novel APC / C C dh1 target. Ct IP interacts with Cdh1 through a conserved KEN box, mutation of which impedes ubiquitylation and downregulation of Ct IP both during G 1 and after DNA damage in G 2 . Finally, we find that abrogating the Ct IP –Cdh1 interaction results in delayed Ct IP clearance from DNA damage foci, increased DNA ‐end resection, and reduced homologous recombination efficiency. Combined, our results highlight the impact of APC / C C dh1 on the maintenance of genome integrity and show that this is, at least partially, achieved by controlling Ct IP stability in a cell cycle‐ and DNA damage‐dependent manner.